# Role of DNA methyltransferases in Huntington's disease

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $427,153

## Abstract

ABSTRACT
Huntington’s disease (HD) is a devastating and invariably fatal neurodegenerative disease characterized
by progressive atrophy and loss of specific neurons in the striatum and cortex, leading to motor, cognitive, and
psychiatric disorders. The underlying disease mechanism remains poorly understood, and currently, no cure
exists for this disease. There is an urgent need to understand the molecular mechanisms driving the death of
HD neurons, so that these mechanisms can be harnessed to save these dying neurons. Transcriptional
dysregulation is an early molecular abnormality in the course of HD and is thought to contribute to
neurodegeneration and disease progression. Although emerging evidence indicates altered patterns of several
different epigenetic modifications in HD, key epigenetic modifications that have a causal role in transcriptional
changes and neurodegeneration remain largely unknown. DNA methylation, a major epigenetic modification,
has recently been shown to be perturbed in mutant Htt-expressing cells and brains of HD patients. Importantly,
our recent findings suggest that DNA methyltransferases (DNMTs), enzymes that catalyze DNA methylation, are
of functional importance in mutant HD protein (huntingtin)-induced neurotoxicity. The fundamental objective of
this proposal is to identify the molecular regulation and role of DNMTs in neuronal dysfunction and death,
using mouse and human cultured neurons as well as mouse models of HD. Our hypothesis is that abnormal
DNA methylation is a dominant epigenetic event in HD, which drives the dysregulation of genes important for
neuronal function and survival, thereby contributing to neuronal dysfunction and death in HD. Targeting this
epigenetic pathway may therefore prevent disease progression. To test this hypothesis, we will pursue the
following specific aims: 1) Determine how mutant Htt induces aberrant DNA methylation with a focus on DNMT
function; 2) Determine the role of DNMTs in HD pathogenesis in mice in vivo; and 3) Identify the mechanism of
DNMT inhibition-mediated neuroprotection in mutant Htt-expressing neurons in vitro and in vivo. We will take
innovative approaches to isolate cell-type specific RNA and DNA from mouse brain to determine HD-specific
DNA methylation and transcription changes in disease-vulnerable neurons in vivo. Our contribution here is
expected to establish the critical role of DNMTs in HD pathogenesis using a disease-relevant neuronal system
and genetic mouse models in vivo, with the long-term goal of discovering potential therapeutic targets to prevent
neurodegeneration in HD. Given the observation of altered transcription and DNA methylation in other
neurodegenerative diseases, psychiatric disorders, aging, and learning and memory, the proposed studies have
implications for a wide-range of human nervous system conditions as well as normal brain function. Together,
our examination of a novel epigenetic mechanism underlying mutant Htt-induced transcriptiona...

## Key facts

- **NIH application ID:** 10160970
- **Project number:** 5R01NS111014-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Hiroko Yano
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $427,153
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10160970

## Citation

> US National Institutes of Health, RePORTER application 10160970, Role of DNA methyltransferases in Huntington's disease (5R01NS111014-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10160970. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*